Inhibition of human immunodeficiency virus 1 replication in vitro by a self-stabilized oligonucleotide with 2'-O-methyl-guanosine-uridine quadruplex motifs

Kuwasaki, Tomoyuki

doi:10.1093/jac/dkg174

Cited by 5 publications

(3 citation statements)

References 31 publications

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“…To reduce possible background signals generated by nuclease activity, the probe was modified to contain 2’-OMe groups and phosphorothioate linkages. The combination of both modifications have been shown to increase resistance of oligonucleotides to nuclease activity [ 27 ]. In vitro tests confirmed that this nuclease-resistant probe (NR- 1 ) behaved similarly to the unmodified probe 1 (Figure D in S1 File ).…”

Section: Resultsmentioning

confidence: 99%

Fluorogenic Real-Time Reporters of DNA Repair by MGMT, a Clinical Predictor of Antitumor Drug Response

et al. 2016

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Common alkylating antitumor drugs, such as temozolomide, trigger their cytotoxicity by methylating the O6-position of guanosine in DNA. However, the therapeutic effect of these drugs is dampened by elevated levels of the DNA repair enzyme, O6-methylguanine DNA methyltransferase (MGMT), which directly reverses this alkylation. As a result, assessing MGMT levels in patient samples provides an important predictor of therapeutic response; however, current methods available to measure this protein are indirect, complex and slow. Here we describe the design and synthesis of fluorescent chemosensors that report directly on MGMT activity in a single step within minutes. The chemosensors incorporate a fluorophore and quencher pair, which become separated by the MGMT dealkylation reaction, yielding light-up responses of up to 55-fold, directly reflecting repair activity. Experiments show that the best-performing probe retains near-native activity at mid-nanomolar concentrations. A nuclease-protected probe, NR-1, was prepared and tested in tumor cell lysates, demonstrating an ability to evaluate relative levels of MGMT repair activity in twenty minutes. In addition, a probe was employed to evaluate inhibitors of MGMT, suggesting utility for discovering new inhibitors in a high-throughput manner. Probe designs such as that of NR-1 may prove valuable to clinicians in selection of patients for alkylating drug therapies and in assessing resistance that arises during treatment.

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Section: Resultsmentioning

confidence: 99%

Fluorogenic Real-Time Reporters of DNA Repair by MGMT, a Clinical Predictor of Antitumor Drug Response

et al. 2016

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“…36 In addition, phosphorothioate oligonucleotides were recently shown to block gp120 interactions and HIV infection in vitro. 49 Other viral infections were also targeted for aptamer intervention, including those owing to hepatitis C virus (HCV), Rous sarcoma virus and Human cytomegalovirus. Aptamers have been generated against the HCV proteins Nonstructural proteins 3 (NS3) and 5B (NS5B) that are required for viral proliferation.…”

Section: Aptamers For Intracellular Targets Are Being Developedmentioning

confidence: 99%

Gene therapy progress and prospects: RNA aptamers

2007

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Aptamers are oligonucleotides evolved in vitro or in nature to bind target ligands with high affinity and specificity. They are emerging as powerful tools in the fields of therapeutics, drug development, target validation and diagnostics. Aptamers are attractive alternatives to antibody-and small-moleculebased therapeutics owing to their stability, low toxicity, low immunogenicity and improved safety. With the recent approval of the first aptamer drug Macugen by the US FDA, there is great impetus to develop therapeutic aptamers that can target a wide array of disease states. The recent demonstration that aptamer activity can be reversed by the administration of a simple antidote greatly enhances the potential value of aptamers as therapeutic agents.

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“…The use of modified chemistries in the thrombin binding aptamer have lead to higher stability(106,(128)(129)(130)(131)231,235), increased binding affinity(106,128), and enhanced biological activity(122,128,231,236,237), including studies in vivo. In a similar manner, studies involving modified nucleic acid chemistries have enhanced the properties of anti-HIV aptamers(106,123,230,(238)(239)(240)(241).…”

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confidence: 95%

Engineering G-quadruplex DNA : a combined computational and experimental study

Lech¹

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Abbreviations 93-del G-quadruplex-forming sequence with anti-HIV activity A Adenine AS1411 G-quadruplex-forming sequence with anti-cancer activity C Cytosine CD Circular cichroism CT Charge transfer D 2 O Deuterium oxide DFT Density functional theory DNA Deoxyribonucleic acid dsDNA Double-stranded deoxyribonucleic acid D.S.S. 4,4-dimethyl-4-silapentane-1-sulfonic acid ET Electron transfer FCD Fragment charge difference FRET Förster resonance energy transfer G Guanine G-tetrad Guanine tetrad G-wire Long molecular wire arranged of stacked G-tetrads Am G 8-amino-guanosine Ben G N2-benzyl-guanine Br G 8-bromo-guanine F G 2'-F-guanosine FANA G 2'-F-ANA-guanosine Hex G N2-6-amino-hexyl-guanine LNA G Locked nucleic acid modified guanosine Met G N2-methyl-guanosine Omet

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Inhibition of human immunodeficiency virus 1 replication in vitro by a self-stabilized oligonucleotide with 2'-O-methyl-guanosine-uridine quadruplex motifs

Cited by 5 publications

References 31 publications

Fluorogenic Real-Time Reporters of DNA Repair by MGMT, a Clinical Predictor of Antitumor Drug Response

Fluorogenic Real-Time Reporters of DNA Repair by MGMT, a Clinical Predictor of Antitumor Drug Response

Gene therapy progress and prospects: RNA aptamers

Engineering G-quadruplex DNA : a combined computational and experimental study

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